Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity

Abstract

A novel series of 1,3-diarylpyrazole derivatives (4-8), analogues to lonazolac, were designed, synthesized, and evaluated for their anti-inflammatory as well as analgesic activities. To target preferential cyclooxygenase-2 (COX-2) inhibitors, the design of these compounds was based upon two different molecular modeling studies. The first study included fit-comparison study of conformational models of compounds 4-8 with a novel validated COX-2 inhibitors hypothesis generated from the corresponding leads I-V using Hip-Hop CATALYST software. The second study included docking study of the designed compounds 4-8 with binding site of COX-1 and COX-2 enzymes using internal coordinate mechanics (ICM)-Pro software. The reported Akaho method was then used to predict the COX-2 preferentiality of the designed compounds. The designed molecules were synthesized and screened for in vivo anti-inflammatory and analgesic activity. Compounds 4a, 6a, and 8b showed high activity in comparison with indomethacin, consistent with virtual molecular modeling studies. © 2009 Birkhäuser Boston.